Non-invasive imaging for determination of global tissue characteristics

ABSTRACT

Evaluating tissue characteristics including identification of injured tissue or alteration of the ratios of native tissue components such as shifting the amounts of normal myocytes and fibrotic tissue in the heart, identifying increases in the amount of extracellular components or fluid (like edema or extracellular matrix proteins), or detecting infiltration of tumor cells or mediators of inflammation into the tissue of interest in a patient, such as a human being, is provided by obtaining a first image of tissue including a region of interest from a first acquisition, and obtaining a second image of the tissue including the region of interest during a second, subsequent acquisition. The subsequent acquisition may be obtained after a period of time to determine if injury has occurred during that period of time. Such a comparison may include comparison of mean, average characteristics, histogram shape, such as skew and kurtosis, or distribution of intensities within the histogram.

RELATED APPLICATIONS AND CLAIM OF PRIORITY

This application is a continuation of U.S. patent application Ser. No.11/051,304 filed Feb. 4, 2005, which issued as U.S. Pat. No. 7,333,845on Feb. 19, 2008, which claims the benefit of priority of U.S.Provisional Patent Application Ser. No. 60/542,547 filed Feb. 6, 2004,the disclosure of which is incorporated herein by reference as if setforth in its entirety.

FIELD OF THE INVENTION

The present invention is related to diagnostics and more particularly tothe detection of global tissue characteristics, such as global tissueinjury.

BACKGROUND OF THE INVENTION

Doxorubicin is an anthracycline antibiotic isolated from a soilmicroorganism. Its anti-tumor effects are related to interactions withthe enzyme topoisomerase-2 and production of double strand DNA breaks.In addition, this agent generates intracellular free radicals that arehighly cytotoxic. Doxorubicin is considered one of the most broadlyactive antitumor agents. Not only is Doxorubicin typically considered animportant element in modern therapy of breast, soft tissue sarcomas andother solid tumors, it is thought to be an important element of curativecombination chemotherapy for acute leukemia, Hodgkin's disease,non-Hodgkin's lymphoma, and many childhood cancers. Thus, for manyindividuals with advanced stages of cancer, Doxorubicin serves as animportant part of their medical regimen.

Administration of Doxorubicin therapy is generally limited in adults andchildren by a cumulative dose dependent cardiotoxicity. Irreversiblecardiomyopathy with serious congestive heart failure can be asignificant risk in patients who receive doses in excess of 500-550mg/m². Unfortunately, the dose that precipitates congestive heartfailure varies widely (ranging from 30-880 mg/m² in a report of 1487patients studied over a seven year period). Those subjects with advancedage or mild reductions in left ventricular systolic function at rest(left ventricular ejection fraction [LVEF]≦50%), are at greatest risk.In western industrialized countries, it is typically older subjects withcancer and some degree of underlying heart disease whom often are ingreatest need for Doxoribicin therapy, but for whom medication may bewithheld due to potential cardiotoxicity.

One method for detection of Doxorubicin-induced cardiomyopathy isintramyocardial biopsy with concomitant left and right ventricularpressure measurements made during cardiac catheterization.Unfortunately, this method involves an invasive procedure and may not bewell suited for repetitive measurements over time. Radionuclideventriculography is also widely used to screen those individuals at riskfor developing Doxoribicin-induced cardiomyopathy. Individuals whodevelop a reduction in LVEF of 10% or greater or those individuals whohave a fall in ejection fraction to lower than 50% during treatment areat greatest risk for developing irreversible cardiotoxicity. While thisinformation is useful as a potential screening technique, for someindividuals, the drop observed in LVEF occurs too late to avert thedevelopment of irreversible cardiomyopathy. For this reason, the totaldose of Doxorubicin may be unduly limited for patients receivingchemotherapy. Importantly for many individuals, Doxorubicin therapy isoften stopped before patients derive maximal benefit of the drugregimen. A noninvasive, widely available method for accurately detectingthose individuals whom go on to develop cardiotoxicity would have markedclinical utility.

During the past 7 years, investigators have established the utility ofMRI for identifying necrotic tissue within the left ventricle inpatients sustaining myocellular injury. This technique incorporates theacquisition of gradient-echo pulse sequences with nonselectivepreparatory radiofrequency pulses after intravenous administration ofGadolinium chelates. In regions of myocardial necrosis, heightenedsignal intensity occurs on images collected 20 minutes after contrastadministration that corresponds to expansion of extracellular volume dueto myocellular membrane disruption and increased capillary permeability.This methodology has been utilized to identify transmural myocellularnecrosis in patients sustaining acute or chronic Q-wave (ST-segmentelevation), and subendocardial (non-transmural) injury in patientssustaining a non-Q-wave (non ST-segment elevation) myocardialinfarction. The amount of necrosis found during MRI displays an inverserelationship with recovery of systolic thickening after coronaryarterial revascularization. The absence of Gadolinium hyperenhancement20 minutes after contrast administration is associated with myocardialviability and subsequent improvement in left ventricular contractionafter sustaining a ST-segment or non ST-segment elevation myocardialinfarction. Although some felt delayed enhancement techniques mayoverestimate regions of myocellular necrosis in the acute infarct,recently, a tagging study in animals indicated that delayed enhancementtechniques do identify early myocellular necrosis after myocardialinfarction (MI). It is believed that, in border zones of infarcts, deadcells may move due to tethering from adjacent live regions.

With MRI, cardiac structure can be imaged and LV function directlyassessed with high temporal and spatial resolution. Since acousticwindows do not limit image acquisition, the utility of MRI is highparticularly in subjects with a large or unusual body habitus. Thisheightened clarity of the images allows investigators to performquantitative measures of LV structure and function with higher precisionthan that achieved with radionuclide and ultrasound techniques. A 5%change in LVEF in patients with reduced LV function can be detected with90% power at a p-value of 0.05 with a sample size of 5 patients pergroup in a parallel study design. Depending upon operator experience,the same 5% change in LVEF requires an echocardiographic assessmentof >100 subjects per group in the same study design. Similarly, theheightened spatial resolution (1 mm² pixel sizes) achieved with delayedenhancement MRI techniques allows for the detection of micro-infarctsthat heretofore may have only been appreciated as cardiac enzymaticelevations detected in serum samples, but not visualized withradionuclide or echocardiographic techniques.

In delayed enhancement imaging a contrast agent is administered to apatient and an image is acquired after the contrast agent has had anopportunity to be distributed to area that is to be imaged such that thecontrast agent remains in injured tissue but does not remain in healthytissue. Such delayed enhancement imaging may be used, for example, toidentify myocardial infarcts as the necrotic tissue of the infarctregion will retain the contrast agent while the contrast agent will bepurged from the healthy tissue. As such, the infarct may appear as alocalized region of higher intensity. Conventionally, delayedenhancement imaging may be used to identify localized regions of tissuedamage in tissues such as cardiac tissue, brain tissue, nerve tissue orthe like.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide methods, systems and/orcomputer program products for evaluating tissue characteristicsincluding identification of injured tissue or alteration of the ratiosof native tissue components such as shifting the amounts of normalmyocytes and fibrotic tissue in the heart, identifying increases in theamount of extracellular components or fluid (like edema or extracellularmatrix proteins), or detecting infiltration of tumor cells or mediatorsof inflammation into the tissue of interest in a patient, such as ahuman being, by obtaining a first image of tissue including a region ofinterest from a first acquisition, for example, after administration ofa contrast agent to the patient, and obtaining a second image of thetissue including the region of interest during a second, subsequentacquisition, for example, after administration of a contrast agent tothe patient. The subsequent acquisition may, for example, be obtainedafter a period of time to determine if injury has occurred during thatperiod of time. The region of interest may include, for example, atleast one of heart, blood, muscle, brain, nerve, skeletal, skeletalmuscle, liver, kidney, lung, pancreas, endocrine, gastrointestinaland/or genitourinary tissue. A global characteristic of the region ofinterest of the first image and of the second image is determined so asto allow a comparison of the global characteristic of the first imageand the second image to determine a potential for a change in globaltissue characteristics such as may be caused, for example, by a globalinjury of the tissue of the region of interest. Such a comparison mayinclude, for example, comparison of mean, average characteristics,histogram shape, such as skew and kurtosis, or distribution ofintensities within the histogram.

In further embodiments of the present invention, the globalcharacteristic is a characteristic of pixels/voxels of the region ofinterest that is based on substantially all of the pixels/voxels in theregion of interest. The global characteristic may be an averageintensity of pixels/voxels in the region of interest. The tissue in theregion of interest may be at least one of cardiac tissue, brain tissueand/or nerve tissue. The first image and the second image may bemagnetic resonance imaging (MRI) images.

While certain embodiments of the present invention are described hereinwith reference to the detection of global tissue characteristics, suchas global injury in a patient, such as a human, additional embodimentsof the present invention may include detection of global injury invertebrate or invertebrate animals, reconstructed tissue and/orsynthetic tissue. Accordingly, certain embodiments of the presentinvention should not be construed as limited to the detection of globalinjury in a human patient.

Particular embodiments of the present invention provide methods, systemsand/or computer program products for detecting global cardiac injury ina patient. A first cardiac image is obtained after administration of acontrast agent to the patient. A second cardiac image is also obtainedafter administration of the contrast agent to the patient. A measure ofintensity of the first cardiac image and a measure of intensity of thesecond cardiac image are determined and the measure of intensity of thefirst cardiac image and the measure of intensity of the second cardiacimage are compared to determine a potential for a global cardiac injury.In certain embodiments of the present invention, an increase in themeasure of intensity of the image indicates the possible presence of aglobal cardiac injury.

In further embodiments of the present invention, the first cardiac imageand the second cardiac image are Magnetic Resonance Imaging (MRI) imagesand/or x-ray Computed Tomography (CT) images. Also, the measure ofintensity of the first cardiac image and the measure of intensity of thesecond cardiac image may be average intensity of the respective images.

In additional embodiments of the present invention, a first image of aregion of interest outside the heart corresponding to the first cardiacimage is also obtained. Correction for variations in pixel intensity innormal myocardium tissue is performed on the first cardiac image usingdata from the first image of a region of interest outside the heart.Similarly, a second image of a region of interest outside the heartcorresponding to the second cardiac image is obtained and correction forvariations in pixel intensity in normal myocardium tissue is performedon the second cardiac image using data from the second image of a regionof interest outside the heart. The measure of intensity of the firstcardiac image and the measure of intensity of the second cardiac imageare determined using the corrected first cardiac image with and thecorrected second cardiac image. For example, the measure of increasedbrightness due to the present of contrast agent may be measured relativeto normal myocardium tissue without contrast agent. The normalmyocardium may not be suppressed to the same degree of darkness in allsubjects and this variation may be accounted.

As will be appreciated by those of skill in the art in light of thepresent disclosure, embodiments of the present invention may be providedas methods, systems and/or computer program products.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram of an MRI system according to embodiments ofthe present invention.

FIG. 2 is a block diagram of a data processing system according toembodiments of the present invention;

FIG. 3 is a block diagram of a data processing system according toembodiments of the present invention;

FIGS. 4A and 4B are flowcharts illustrating operations according tocertain embodiments of the present invention;

FIG. 5 is a flowchart illustrating operations according to certainembodiments of the present invention;

FIG. 6 is a 3-Dimensional depiction of three short axis planes of a leftventricle;

FIG. 7 are delayed enhancement MRI images in a middle (mid-plane) shortaxis view of the left ventricle with corresponding intensity histograms;

FIG. 8 are intensity histograms of voxels within a region of interest(ROI);

FIG. 9 is a graph of auto-correlation measures for study patients;

FIG. 10 are images and mean voxel intensities for two separate patients;

FIG. 11 are middle short axis views acquired twenty-one days apart for apatient; and

FIG. 12 is a screen capture of image planning software for reproducingslice positions.

DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described more fully hereinafter withreference to the accompanying drawings, in which embodiments of theinvention are shown. However, this invention should not be construed aslimited to the embodiments set forth herein. Rather, these embodimentsare provided so that this disclosure will be thorough and complete, andwill fully convey the scope of the invention to those skilled in theart. Like numbers refer to like elements throughout. As used herein theterm “and/or” includes any and all combinations of one or more of theassociated listed items.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, integers, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, integers, steps, operations, elements,components, and/or groups thereof.

It will be understood that, although the terms first, second, etc. maybe used herein to describe various elements, components, regions, layersand/or sections, these elements, components, regions, layers and/orsections should not be limited by these terms. These terms are only usedto distinguish one element, component, region, layer or section fromanother region, layer or section. Thus, a first element, component,region, layer or section discussed below could be termed a secondelement, component, region, layer or section without departing from theteachings of the present invention.

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the relevant art and thepresent disclosure and will not be interpreted in an idealized or overlyformal sense unless expressly so defined herein.

As will be appreciated by one of skill in the art, the present inventionmay be embodied as methods, systems, or computer program products.Accordingly, the present invention may take the form of an entirelyhardware embodiment, an entirely software embodiment or an embodimentcombining software and hardware aspects all generally referred to hereinas a “circuit” or “module.” Furthermore, the present invention may takethe form of a computer program product on a computer-usable storagemedium having computer-usable program code embodied in the medium. Anysuitable computer readable medium may be utilized including hard disks,CD-ROMs, optical storage devices, a transmission media such as thosesupporting the Internet or an intranet, or magnetic storage devices.

Computer program code for carrying out operations of the presentinvention may be written in an object oriented programming language suchas Java®, Smalltalk or C++. However, the computer program code forcarrying out operations of the present invention may also be written inconventional procedural programming languages, such as the “C”programming language. The program code may execute entirely on a user'scomputer, partly on the user's computer, as a stand-alone softwarepackage, partly on the user's computer and partly on a remote computeror entirely on the remote computer. In the latter scenario, the remotecomputer may be connected to the user's computer through a local areanetwork (LAN) or a wide area network (WAN), or the connection may bemade to an external computer (for example, through the Internet using anInternet Service Provider). Furthermore, the user's computer, the remotecomputer, or both, may be integrated into other systems, such as an MRIsystem and/or X-Ray Computed Tomography system.

The present invention is described below with reference to flowchartillustrations and/or block diagrams of methods, apparatus (systems) andcomputer program products according to embodiments of the invention. Itwill be understood that each block of the flowchart illustrations and/orblock diagrams, and combinations of blocks in the flowchartillustrations and/or block diagrams, can be implemented by computerprogram instructions. These computer program instructions may beprovided to a processor of a general purpose computer, special purposecomputer, or other programmable data processing apparatus to produce amachine, such that the instructions, which execute via the processor ofthe computer or other programmable data processing apparatus, createmeans for implementing the functions/acts specified in the flowchartand/or block diagram block or blocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including instruction meanswhich implement the function/act specified in the flowchart and/or blockdiagram block or blocks.

The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing the functions/acts specified inthe flowchart and/or block diagram block or blocks.

MRI procedures are well established for identifying myocellular injuryand LVEF in patients with ischemic cardiomyopathy secondary to coronaryarteriosclerosis. Such procedures may identify localized cardiac injury.However, it is believed that such non-invasive imaging has not beenutilized to identify global cardiac injury in patients withcardiomyopathy secondary to chemotherapy administration. Early detectionof myocellular injury could offer an opportunity to adjust medicationdosages and reduce and/or minimize the cardio-toxic effects associatedwith chemotherapy. In this manner, maximal doses of chemotherapy couldbe administered to patients in the absence of myocellular injury and thedesired effect of the chemotherapy medications may be more fullyrealized. While embodiments of the present invention may be particularlyuseful in doxoribicin therapy, embodiments of the present invention mayalso be utilized in other chemical therapies or regimens, and/ordiagnostic environments where global cardiac injury is to be detected.

Embodiments of the present invention provide for detection of a changein tissue characteristics such as may result from an injury utilizing acomparison of a global characteristic of a region of interest in animage of the region of interest. A global characteristic of a region ofinterest is a characteristic of the region of interest that is based onone or more characteristics of all or substantially all of thepixels/voxels of the region of interest. Thus, in certain embodiments ofthe present invention, the global characteristic may be substantiallyindependent of the location of pixels within the region of interest.Examples of a global characteristic may include but are not limited to astatistical analysis of a characteristic of pixels/voxels in the regionof interest such as average intensity, a histogram of intensity valuesor other statistical analysis. The use of a comparison of globalcharacteristics of images may allow for detection of injury where thepattern of injury is random and/or is not detectable at the resolutionof the images that are compared. Embodiments of the present inventionmay also use global characteristics, not only to detect injury to anarea, but also to detect abnormal accumulation of materials that are notfound in their normal ratios within native tissue. Embodiments of thepresent invention may also be used with molecular imaging strategies,for example, directing the contrast with molecular recognition sites toareas of tissue and quantifying the presence of a target or molecularprocess. Thus, particular embodiments of the present invention may haveapplication in detecting cancer, inflammation, infection, swelling oredema, scar tissue, etc. Also, embodiments of the present inventioncould be used to define metabolic pathways that are functioning withintissue in an organ system. Particular embodiments of the presentinvention provide for the detection of global cardiac injury utilizingnon-invasive imaging after administration of a contrast agent.Non-invasive techniques suitable for use in embodiments of the presentinvention include Magnetic Resonance Imaging (MRI), ultrasound, x-raycomputed tomography (CT), single photon emission computed tomography(SPECT) and/or positron emission tomography (PET). Comparisons may bemade between a first or baseline image and a second image and thecontrast of the image analyzed to detect the presence of global cardiacinjury. As used herein, the term image refers to a spatial signal thatmay be evaluated to obtain a desired measure of signal intensity.

As used herein, the term “global injury” refers to a change in tissuecomposition and/or function that is in a substantially randomlydistributed pattern and/or in a pattern that is not detectable at theresolution of the images that are analyzed to detect the injury. Thus,for example, “global cardiac injury” may refer to cardiac injury and/orreplacement of native myocardial tissue with fibrous tissue, such asscar tissue, that results in necrosis and/or fibrosis in a substantiallyrandomly distributed pattern and/or in a pattern that is not detectableat the resolution of the images that are analyzed to detect the injury.Global cardiac injury that may be detected by intensity analysisaccording to embodiments of the present invention may include, forexample, viral cardiomyopathy, alcoholic cardiomyopathy, postpartumcardiomyopathy and/or idiopathic dilated cardiomyopathy. A global injurymay also include disproportionate amounts of other abnormalities such asedema (extra fluid), fibrosis (scar tissue), etc. Thus, embodiments ofthe present invention may provide for the detection of global abnormaltissue.

Contrast agents suitable for use in embodiments of the present inventionmay include paramagnetic lanthanide chelates and/or paramagneticlanthanide linked to a macromolecule, such as gadolinium DPTA. Otherexamples of MR contrast for perfusion imaging include the application ofsusceptibility agents containing iron oxide or dysprosium that introducelocal inhomogeneity into the magnetic field by causing largefluctuations in the magnetic moment between blood and intracellularcompartments. Imaging after the introduction of other drugs that inducecardiomyopathy, such as cocaine and/or alcohol could also be performed.These fluctuations result in the shortening of T2-star of neighboringhydrogen nuclei leading to loss of signal intensity. In particularembodiments of the present invention, the same contrast agent isutilized for each image.

Additionally, certain embodiments of the present invention may providefor contrast/intensity analysis without the administration of a contrastagent. For example, another example of perfusion imaging is theassessment of myocardial perfusion or injury without the administrationof a contrast agent using a blood oxygen level dependent (BOLD) cardiacimaging via a T2-prepared true FISP, or 3D-T2-weighted sequencestrategy. Other techniques use endogenous contrast including spinlabeling and magnetization transfer contrast. Thus, in certainembodiments of the present invention, a global characteristic of aregion of interest may be detected without the administration of acontrast agent.

An exemplary system 10 according to embodiments of the present inventionis illustrated in FIG. 1. As seen in FIG. 1, an intensity analysis/MRIsystem 10 includes an MRI acquisition system 11 that may include an MRIcontrol system circuit 12, an MRI pulse excitation system circuit 14 andan MRI signal measurement system circuit 16. The MRI control systemcircuit 12 controls operations of the MRI acquisition system 11 toobtain and provide MRI images during a cardiac cycle or portions thereofof a patient. The MRI control system circuit 12 may also assemble andtransmit the acquired images to a workstation 20 or other such dataprocessing system for further analysis and/or display. The workstation20 may be in an MRI suite or may be remote from the MRI suite. The MRIpulse excitation system circuit 14 and the MRI signal measurement systemcircuit 16 are controlled to acquire MRI signals that may provide MRIimages of the heart of a patient.

Conventional MRI systems, such as those provided by General ElectricMedical Systems, Siemens, Philips, Varian, Bruker, Marconi, Hitachi andToshiba may be utilized to provide the desired MRI image framescollected after administration of a contrast agent.

While an exemplary intensity analysis/MRI system is illustrated in FIG.1 and described herein with a particular division of functions and/oroperations, as will be appreciated by those of skill in the art, otherdivisions of functions and/or operations may be utilized while stillbenefiting from the teachings of the present invention. For example, theMRI control system circuit 12 could be combined with either the MRIpulse excitation system circuit 14 or the MRI signal measurement systemcircuit 16. Thus, the present invention should not be construed aslimited to a particular architecture or division of MRIfunctions/operations but is intended to cover any architecture ordivision of functions/operations capable of carrying out the operationsdescribed herein.

FIG. 2 illustrates an exemplary embodiment of a data processing system230 suitable for providing a workstation 20 and/or MRI control systemcircuit 12 in accordance with embodiments of the present invention. Thedata processing system 230 typically includes input device(s) 232 suchas a keyboard or keypad, a display 234, and a memory 236 thatcommunicate with a processor 238. The data processing system 230 mayfurther include a speaker 244, and an I/O data port(s) 246 that alsocommunicate with the processor 238. The I/O data ports 246 can be usedto transfer information between the data processing system 230 andanother computer system or a network. These components may beconventional components such as those used in many conventional dataprocessing systems that may be configured to operate as describedherein.

FIG. 3 is a block diagram of embodiments of data processing systems thatillustrates systems, methods, and computer program products inaccordance with embodiments of the present invention. The processor 238communicates with the memory 236 via an address/data bus 348. Theprocessor 238 can be any commercially available or custommicroprocessor. The memory 236 is representative of the overallhierarchy of memory devices containing the software and data used toimplement the functionality of the data processing system 230. Thememory 236 can include, but is not limited to, the following types ofdevices: cache, ROM, PROM, EPROM, EEPROM, flash memory, SRAM, and DRAM.

As shown in FIG. 3, the memory 236 may include several categories ofsoftware and/or data used in the data processing system 230: theoperating system 352; the application programs 354; the input/output(I/O) device drivers 358; and the data 356. As will be appreciated bythose of skill in the art, the operating system 352 may be any operatingsystem suitable for use with a data processing system, such as OS/2, AIXor System390 from International Business Machines Corporation, Armonk,N.Y., Windows95, Windows98, Windows2000, WindowsNT or WindowsXP fromMicrosoft Corporation, Redmond, Wash., Unix or Linux. The operatingsystems may be configured to support an TCP/IP-based or other suchnetwork communication protocol connection. The I/O device drivers 358typically include software routines accessed through the operatingsystem 352 by the application programs 354 to communicate with devicessuch as the I/O data port(s) 246 and certain memory 236 components. Theapplication programs 354 are illustrative of the programs that implementthe various features of the data processing system 230 and preferablyinclude at least one application that supports operations according toembodiments of the present invention. Finally, the data 356 representsthe static and dynamic data used by the application programs 354, theoperating system 352, the I/O device drivers 358, and other softwareprograms that may reside in the memory 236.

As is further seen in FIG. 3, the application programs 354 may include aintensity analysis application 360. The intensity analysis application360 may carry out the operations described herein for evaluating imagesto detect changes in intensity that may be associated with globalcardiac injury. The data portion 356 of memory 236, as shown in theembodiments of FIG. 3, may include image data 362, such as MRI imagedata that includes first and second images of tissue of a region ofinterest for comparison.

While the present invention is illustrated, for example, with referenceto the intensity analysis application 360 being an application programin FIG. 3, as will be appreciated by those of skill in the art, otherconfigurations may also be utilized while still benefiting from theteachings of the present invention. For example, the intensity analysisapplication 360 may also be incorporated into the operating system 352,the I/O device drivers 358 or other such logical division of the dataprocessing system 230. Thus, the present invention should not beconstrued as limited to the configuration of FIG. 3 but is intended toencompass any configuration capable of carrying out the operationsdescribed herein.

FIG. 4A illustrates operations according to particular embodiments ofthe present invention. As seen in FIG. 4A, a first image of a region ofinterest of tissue of a patient is obtained (block 400). An image may beobtained, for example, by acquisition of the image from an imagingsystem, such as the imaging systems discussed above, and/or by obtainingthe image from a database, file or other storage of the image data. Forexample, a patient's images may be maintained in a historical databasefor subsequent recall as a first image for comparison. The region ofinterest of tissue in a patient that is imaged may, for example, includeheart, blood, muscle, brain, nerve, skeletal, skeletal muscle, liver,kidney, lung, pancreas, endocrine, gastrointestinal and/or genitourinarytissue. In particular embodiments of the present invention, the tissuemay be human tissue. In other embodiments, the tissue may be animaltissue.

As is further illustrated in FIG. 4A, a second image of the tissue inthe region of interest for comparison to the first image is obtainedafter a period of time, such as hours, days, weeks, months or even years(block 402). The second image for comparison reflects any change in thecharacteristics of the tissue in the region of interest. The second,comparison image may be acquired and registered (taken at the same slicelocations) with the corresponding first image. The second image may alsobe obtained as described above with reference to the first image. Thus,for example, comparison images may be historical images as well asrecently acquired images.

The first image and the second image are evaluated to determine one ormore global characteristics of the images (block 404). The globalcharacteristic of the images may, for example, be an average intensityof pixels/voxels in the region of interest. The global characteristiccould also be a statistical analysis of the pixels/voxels in the regionof interest. For example, the standard deviation, mean value or otherstatistical analysis of the pixels/voxels in the region of interestcould be determined. Also, a histogram of a characteristic of thepixels/voxels in the region of interest could be provided as a globalcharacteristic. The characteristic of the pixels/voxels that isevaluated to provide the global characteristic may include intensity,color, saturation and/or other characteristics of individualpixels/voxels as well as relative characteristics of multiplepixels/voxels, such as contrast ratios or the like.

The results of this evaluation are provided to a user or may be providedfor further analysis (block 406). For example, a comparison of the firstimage and the second image may be performed and a difference in averageintensity may be provided as results to a user. Furthermore, a histogramof the characteristic and/or differences in the characteristic betweenthe baseline and comparison images may be determined and provided as aresult. Additionally, the histogram could be pattern matched to alibrary of histogram profiles that are characteristic of particularinjuries, diseases and/or conditions. The results of the determinationmay, for example, be provided as part of a graphic user interface

The results of the evaluation of the global characteristic of the imageof the tissue in the region of interest may be utilized in thedetection, perhaps the early detection, of change in tissuecharacteristics such as may result, for example, from injury to thetissue or other conditions as discussed above. Such a globalcharacteristic evaluation may be suitable in detecting tissuecharacteristics that result in a random pattern of different tissuecharacteristics in the region of interest or that are imaged at aresolution where a pattern of the tissue characteristic cannot bedetected.

FIG. 4B illustrates operations according to particular embodiments ofthe present invention utilizing administration of a contrast agent. Asseen in FIG. 4B, a baseline image of a region of interest of tissue of apatient is obtained (block 450). An image may be obtained, for example,by acquisition of the image from an imaging system, such as the MRIsystem illustrated in FIG. 1, and/or by obtaining the image from adatabase, file or other storage of the image data. For example, apatient's images may be maintained in a historical database forsubsequent recall as a baseline image for comparison. The baseline imagemay be an image taken without administration of a contrast agent, afteradministration of a contrast agent and/or a period of time, such astwenty minutes, after administration of the contrast agent. The regionof interest of tissue in a patient that is imaged may, for example,include heart, blood, muscle, brain, nerve, skeletal, skeletal muscle,liver, kidney, lung, pancreas, endocrine, gastrointestinal and/orgenitourinary tissue. In particular embodiments of the presentinvention, the tissue may be human tissue. In other embodiments, thetissue may be animal tissue.

As is further illustrated in FIG. 4B, an image of the tissue in theregion of interest for comparison to the baseline image is obtainedafter administration of a contrast agent (block 452). The image forcomparison reflects the effect of the contrast agent on the tissue inthe region of interest. In particular embodiments of the presentinvention, the image may be a myocardial delayed enhancement (MDE)image. The comparison image may be acquired and registered (taken at thesame slice locations) with the corresponding baseline image. Thecomparison image may also be obtained as described above with referenceto the baseline image. Thus, for example, comparison images may behistorical images as well as recently acquired images.

The baseline image and the comparison image are evaluated to determineone or more global characteristics of the images (block 454). The globalcharacteristic of the images may, for example, be an average intensityof pixels/voxels in the region of interest. The global characteristiccould also be a statistical analysis of the pixels/voxels in the regionof interest. For example, the standard deviation, mean value or otherstatistical analysis of the pixels/voxels in the region of interestcould be determined. Also, a histogram of a characteristic of thepixels/voxels in the region of interest could be provided as a globalcharacteristic. The characteristic of the pixels/voxels that isevaluated to provide the global characteristic may include intensity,color, saturation and/or other characteristics of individualpixels/voxels as well as relative characteristics of multiplepixels/voxels, such as contrast ratios or the like.

The results of this evaluation are provided to a user or may be providedfor further analysis (block 456). For example, a comparison of thebaseline image and the comparison image may be performed and adifference in average intensity may be provided as results to a user.Furthermore, a histogram of the characteristic and/or differences in thecharacteristic between the baseline and comparison images may bedetermined and provided as a result. Additionally, the histogram couldbe pattern matched to a library of histogram profiles that arecharacteristic of particular injuries, diseases and/or conditions. Theresults of the determination may, for example, be provided as part of agraphic user interface

The results of the evaluation of the global characteristic of the imageof the tissue in the region of interest may be utilized in thedetection, perhaps the early detection, of injury to the tissue. Suchdetection may be provided for injuries that result in a differentconcentration of contrast agent being present in injured versus healthytissue. Such a global characteristic evaluation may be suitable indetecting injuries that result in a random pattern of injured tissue inthe region of interest or that are imaged at a resolution where apattern of the injured tissue cannot be detected. Thus, for example,with a 1.5 Tesla MRI imaging system, a typical myocardial infarct wouldnot be considered a global image and the detection and location ofincreased intensity in an image in the location of the infarct would notbe considered a random pattern of injured tissue or a pattern of injuredtissue that could not be detected at the resolution of the MRI imagingsystem.

FIG. 5 illustrates operations according to particular embodiments of thepresent invention. As seen in FIG. 5, a contrast agent is administeredto a patient (block 400) and an image of at least a portion of thepatient's heart is acquired (block 402). In particular embodiments ofthe present invention, the acquired perfusion image may be a myocardialdelayed enhancement (MDE) image. In MDE, 20 minutes after a contrastagent, such as gadolinium DPTA, is administered, some of it has leakedinto necrotic (dead) tissue and will appear bright (hence, delayedenhancement). These images may be acquired and registered (taken at thesame slice locations) with the corresponding baseline perfusion images.

The acquired image is evaluated and the intensity of the image iscompared to a baseline image (block 404). The baseline image is an imageof the patient's heart and may be a previously acquired image that wasalso acquired after administration of a contrast agent. The baselineimage may have been acquired prior to administration of a treatmentregimen or may be an image acquired at an earlier evaluation. Thecomparison of images may be a comparison of average intensity of theimages as discussed in more detail below. If the intensity of the imagehas not increased in comparison to the baseline image (block 406), thenan indication that a global cardiac injury is not present may beprovided (block 408). If the intensity of the image has increased incomparison to the baseline image (block 406), then an indication that aglobal cardiac injury may be present may be provided (block 410).

In still further embodiments of the present invention, the evaluation ofglobal image characteristics, such as the intensity of the cardiacimages, may be performed automatically or partially automaticallyutilizing image processing techniques. An automatic comparison may, forexample, also include registration of the differing images to eachother. Such a registration may be provided utilizing conventionalpattern recognition and/or alignment techniques such that correspondingpixels of the images or portions of the images are each associated withapproximately the same physical location within the patient.

In particular embodiments of the present invention, a patient may betaken to the MRI suite where they will be placed supine on the MRI tableand ECG leads and respiratory gating bellows applied. MRI scans may beperformed on, for example, a 1.5 Tesla GE CV_(i) scanner with a phasedarray surface coil applied around the chest to optimize signal to noiseor other MRI scanner. Images may be acquired using a fast gradient echotechnique, with the repetition time (TR) and echo time (TE) based on theR-R interval of the subject. Multislice coronal, gradient echo sequencesmay be used to obtain scout images of the chest and locate the leftventricle. Subjects may be injected intravenously with a gadoliniumcontrast agent (0.2 mmole/kg Gadoteridol (Prohance, Bracco Diagnostics,Princeton, N.J.). The time of this injection may be recorded.

About twenty minutes from the time of the contrast injection, threeshort axis views (basal, middle, and apical) delayed enhancement imagesmay be acquired using a fast gradient echo preceded by a nonselectivesaturation pulse. Landmarks for these acquisitions may be measured offof the coronary sinus within the atrio-ventricular groove extendinghorizontally across the mitral valve annulus. These images may beacquired using a 38 cm field of view, 24 views per segment, 8 mm slicethickness, 2 NEX, 256×256 imaging matrix, and a 0.75 rectangular fieldof view. The inversion time (TI) for the delayed enhancement images maybe adjusted 140 to 160 msec to provide a uniform dark background.Additionally, in these three short axis slice positions, afast-gradient-recalled echo pulse sequence may be used with phase-encodeordering. These images may be subjected to phase-sensitivereconstruction that reduces the variation in apparent contrast intensitythat is observed in the magnitude images as TI is changed. In addition,the phase-sensitive reconstruction may decrease the sensitivity tochanges in tissue T₁ with increasing delay from the Gadolinium contrastinjection.

Upon completion of the image acquisition, the locations, measurements,and representative images may be transferred electronically to adatabase. This information may be available to the MRI technologist viaa PC workstation at the time of each scan and facilitate the relocationof slice positions (registration) on subsequent studies.

FIG. 12 illustrates a screen capture of software for planning imageslices. Such software may provide electronic copies of image planningslices and positioning coordinates that are saved for retrieval duringsubsequent visits in a study. This has the effect of improving theability of the MRI technologist to reproduce slice positions from theprevious visits. In the example of FIG. 12, a long-axis view of theheart with a resultant delayed enhancement short axis view is shown.

On the delayed enhancement acquisitions, regions of interest (ROIs)encompassing the LV myocardium on all of the multi-slice acquisitionsmay be determined. High signal intensities associated with the bloodpool within the LV cavity may be avoided. The signal intensity andlocation (x, y, and z coordinates) of each (or selected) voxel withinthe ROI's may be recorded from both baseline and delayed enhancementimages. Values may also be derived from subtracting the mean intensityfor a separate ROI, for example, without contrast agent, from theintensities by using a separate ROI within the air/space outside of thebody. The ROI's may be utilized as discussed below in the Examples indetermining a change in intensity between two images.

While embodiments of the present invention have been described abovewith respect to particular views, regions, areas and/or slices of theheart, other views, regions, areas and/or slices of the heart may alsobe utilized. Furthermore, fewer or greater than three slices may beutilized. Additionally, the images may be taken along the long or shortaxis of the heart. Accordingly, certain embodiments of the presentinvention should not be construed as limited to the particular views ofthe heart but may include any view and/or number of views of the heartthat allow for intensity analysis to detect global cardiac injury.

Typically, a first baseline image will be obtained prior to or early intreatment or as an initial reference point in diagnosis of change incardiac condition. Subsequent images for comparison may be taken daily,weekly or at other fixed or variable interval(s) or prior to or afterplanned treatment, such as a cytotoxic treatment.

The invention will now be described in more detail in the followingnon-limiting examples.

EXAMPLES

As briefly mentioned above, conventionally, identification ofmyocellular necrosis in patients with an ischemic cardiomyopathy hasbeen performed by locating the voxels with a signal intensity >2standard deviations above the background intensity within non-enhancedLV myocardium. The amount of necrosis is quantified by determining thetransmural extent of hyperenhancement expressed as a ratio of the numberof high intensity pixels extending linearly from the endocardial to theepicardial surface relative to the total distance from the endocardiumto epicardium. Since myocardial necrosis proceeds in a wavefront fromthe endocardial to epicardial surface in the setting of reduced coronaryarterial blood flow, this method is useful for assessing the amount ofnecrosis after myocardial infarction.

However, this method may not be as well suited for a process that causesnecrosis to susceptible tissue throughout the LV myocardium in arandomly distributed pattern (e.g. a global injury). To overcome thislimitation, voxels, and in some embodiments all the voxels, within threeshort axis slice positions (apex, middle, and base) within the LV may besampled and the intensity, x, y, and z coordinates of each voxelidentified in 3-dimensional space (FIG. 6). FIG. 6 is a 3-Dimensionaldepiction of 3 short axis (basal, middle, and apical) planes of the leftventricle. In each plane, the grid of small boxes on the face of eachslice demarcate the voxels. During analysis, the image intensity of eachvoxel and the x, y, and z coordinates are recorded. In this way, highintensity pixels identified with the delayed enhancement techniqueassociated with a randomly distributed process causing myocellularnecrosis (white splotches on images) can be characterized.

Correction for variations in the intensity of voxels in the images mayalso be identified by determining the intensity of voxels within atarget region, typically, a 1 cm diameter circular region of interest(ROI) placed outside the heart. For each apical, middle, and basalslice, the number of pixels at a given intensity may be determined andthe intensity from the ROI external to the heart subtracted from thepixels. In certain embodiments, for each slice, the mean intensity ofall voxels and the peak voxel intensity in the highest 40% of thedistribution may be determined (FIG. 6). In this way, regions of highintensity pixels may be identified relative to their location within theleft ventricle.

FIG. 7 are exemplary delayed enhancement MR images (top panels) in amiddle short axis view of the LV. The myocardium is gray and the bloodpool is white. The number (y-axis) and intensity (x-axis) of voxelswithin the ROI (red-line) 20 minutes after contrast administration aredisplayed in the bottom panels. The contrast is taken up by allmyocytes, but 20 minutes after administration, it is not cleared fromnecrotic cells. As shown, the mean intensity of contrast uptake is lowin the healthy normal patient (far left) and highest in the patient withan infarct (third from left). An intermediate mean intensity isdisplayed on the histogram associated with the Doxorubicincardiomyopathy patient (second from left).

To determine the utility of MRI assessments of the location andmagnitude of gadolinium contrast uptake 20 minutes after intravenousadministration, a cross-sectional study in 4 groups of age (range 35 to50 years) and gender matched participants was performed. These included:

-   -   a) (Group I): 4 subjects (1M,3F) without medical illness, taking        no cardiac medications, and with normal LV systolic and        diastolic function by MRI,

b) (Group II): 3 patients (3F) without coronary arterial luminalnarrowings on contrast coronary angiography but with poor LV ejectionfraction (<35%) and congestive heart failure secondary to Doxorubicinadministration,

-   -   c) (Group III): 3 patients (2M,1F) without coronary arterial        luminal narrowings on contrast coronary angiography and with        poor LV ejection fraction (<35%) and congestive heart failure        secondary to an idiopathic dilated cardiomyopathy, and    -   d) (Group IV): 3 patients (2M, 1F) with LV dysfunction secondary        to an ischemic cardiomyopathy and prior ST-segment elevation        myocardial infarction.

A middle short axis image and the distribution of intensities of voxelswithin the image from one subject in each group is displayed in FIG. 7,and the distributions of voxel intensities within all of the slices fromall of the participants are displayed in FIG. 8.

In FIG. 8, the percentage (y-axis) and intensity (x-axis) of voxelswithin ROIs from all participants in the cross-sectional sampling ofsubjects 20 minutes after contrast administration. As displayed in FIG.7, an increased percentage of intensities in the 15 to 30 range aredisplayed in patients with cardiomyopathy due to chemotherapyadministration compared to normal age matched controls. This pattern ofintensities appears different from that seen in patients with anischemic cardiomyopathy.

To determine the relationship between the pattern of high intensitypixels within each slice of the left ventricle, an auto-correlationstatistic was used. The serial auto-correlation measure (I) is definedas follows. Let δ_(ij) be a weighting function of the distance betweenpixels i and j, n be the number of pixels, and x_(i) be the intensityfor the i^(th) pixel. Then define

$I = {n{\frac{\sum\limits_{ij}{{\delta_{ij}\left( {x_{i} - \overset{\_}{x}} \right)}\left( {x_{j} - \overset{\_}{x}} \right)}}{\left( {\sum\limits_{ij}\delta_{ij}} \right)\left( {\sum\limits_{i}\left( {x_{i} - \overset{\_}{x}} \right)^{2}} \right)}.}}$I is a measure of serial autocorrelation and is higher when adjacentpixels are both higher or lower than the mean (Ripley, 1981). Inpractice, the expression

$\delta_{ij} = {\exp\left( {{- \frac{1}{2}}{d\left( {x_{i},x_{j}} \right)}} \right)}$has been used, where d(x_(i), x_(j)) is the Euclidian distance betweenpoints x_(i) and x_(j).

Using this form of analysis a high number indicates pattern clusteringwithin the ROI, and a low number is more indicative of a randomassociation. As shown in FIG. 9, the heightened signal intensitiesassociated with MI were tightly clustered in the infarct zone; whereasthose associated with Doxorubicin toxicity were scattered throughout theLV. The pattern of contrast uptake within the LV in patients withcardiomyopathy secondary to Doxorubicin administration was random andsignificantly different (p<0.001) from the pattern of high signalintensity voxels associated with myocardial necrosis secondary tomyocardial infarction.

To determine if contrast enhancement is associated with a fall in LVEFin individuals receiving chemotherapy, a baseline MRI examination wasperformed in patients prior to initiation of chemotherapy and thenadditional MRI examinations were performed according to the researchstudy protocol. Echocardiography exams were also performed to monitorpatient left ventricular function between MRI examinations. One subjecthad developed dyspnea and received a echocardiogram to determine LVEF.The subject had a fall in LVEF from 55% to 48%. This individualunderwent MRI testing and image analysis. The image analysis of thissubject was compared to one other subject who had not developed a dropin LVEF during course of chemotherapy regimen. Images and the voxelintensities in the middle short axis view from the patients aredisplayed in FIG. 10.

FIG. 10 illustrates images and mean voxel intensities at two time pointsin two separate patients while receiving chemotherapy, one of whichdeveloped dyspnea during the course of chemotherapy. Pre-treatmentimages in both patients are displayed on the left and post treatmentimages are displayed on the right. Mean voxel intensities for the ROIwithin the image are displayed under the image. In patient 1 thatdeveloped a fall in LVEF (Top panels), heightened contrast uptake andsignal intensity occurred in the second exam after receipt of 400 mg/m²of anthracyclines for treatment of breast cancer. In the second patient(Bottom panels), no fall in LVEF occurred and the uptake pattern showedno significant change. As shown, in the individual with a fall in LVEF,there was a significant increase in the intensity of voxels within theLV in the second exam compared to the first, whereas in the individualwithout a fall in LVEF, there was no marked change on the second exam.

To determine the variance of MRI delayed enhancement voxel intensitiesover time in participants without a substantive change in their medicalcondition, four individuals were studied twice after contrastadministration over a two week period. Images from one of theparticipants are shown in FIG. 11, and data from both sample points inall four individuals is shown in Table 1.

TABLE 1 In four participants, MRI intensity (mean ± standard deviation)and LVEF. Day 1 Day 21 LVEF 0.67 ± 0.04 0.64 ± 0.04 p = NS Meanintensity 6.64 ± 1.15 6.60 ± 0.96 p = NS

FIG. 11 illustrates middle left ventricular short axis views acquired 21days apart in an individual without a change in their condition. Notethe near exact replication of the slice position on the secondacquisition using software discussed elsewhere herein. Twenty minutesafter contrast administration, the signal intensity within the ROIs wasnot significantly different, 5.8 versus 6.1 (p=NS). MRI examinationswith this technique may be acquired reproducibly over time.

There was little change in the uptake patterns of contrast in thesubjects between the first and second exam, and for the four individualsmeasured at two points in time, the correlation between the 2measurements was excellent (y=0.87x+1.2, R²=0.96).

Based on the above data, it appears that delayed enhancement MRI uptakepatterns of contrast are elevated in patients with cardiomyopathysecondary to chemotherapy induced cardiotoxicity compared to age andgender matched control subjects. The pattern of this contrast uptake isdiffuse and randomly distributed throughout the left ventricle in afashion that is distinctly different from myocellular injury observed inpatients sustaining a myocardial infarction. In the project involvingtwo patients receiving chemotherapy, heightened contrast uptake occurredcoincident with a fall in LVEF in one, but not the other that did notdevelop a fall in LVEF. Such a methodology and analysis methods may behighly reproducible and exhibit low intraobserver variability.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims.

That which is claimed is:
 1. A method of evaluating a potential of aglobal injury of tissue of a patient, comprising: electronicallyregistering a region of interest in a first image with a correspondingregion of interest in a second image obtained subsequent to the firstimage; electronically determining a global intensity characteristic ofthe region of interest based on image data from the first and secondimages, wherein the determining the global intensity characteristiccomprises evaluating at least one of skew, kurtosis, or standarddeviation of at least one property of pixels/voxels of the region ofinterest and/or at least one of a shape or distribution of at least onepixel/voxel intensity histogram associated with the region of interest;electronically applying an autocorrelation statistic (I) to determine arelationship between a pattern of pixel parameters within a threedimensional tissue volume of a ROI (region of interest) to evaluatewhether the pattern is clustered or randomly distributed or diffuse; andelectronically displaying to a user a likelihood of at least one of anactual or a potential for a global injury of tissue in the region ofinterest based on the determined global intensity characteristic,wherein the global injury is due to a change in tissue compositionand/or function that is in a scattered, diffuse and/or randomlydistributed pattern in the region of interest.
 2. The method of claim 1,wherein the first and the second images comprise at least one ofMagnetic Resonance Imaging (MRI) images, X-ray computed tomography (CT)images, ultrasound images, single photon emission computed tomography(SPECT) images and/or positron emission tomography (PET) images.
 3. Themethod of claim 1, wherein each of the first and second images comprisea plurality of MM slices.
 4. The method of claim 1, wherein at least oneof the first and second images comprises MRI slices, and whereinelectronically determining the global intensity characteristic includeselectronically evaluating the shape or distribution of at least onepixel/voxel intensity histogram.
 5. The method of claim 1, wherein thetissue includes at least one of heart, blood, muscle, brain, nerve,skeletal, skeletal muscle, liver, kidney, lung, pancreas, endocrine,gastrointestinal and/or genitourinary tissue.
 6. The method of claim 1,wherein the images are cardiac MRI images, wherein the electronicallydetermining step that determines the likelihood of at least one of anactual or a potential for a global injury determines the likelihood of afuture onset of global cardiac injury including at least one of viralcardiomyopathy, alcoholic cardiomyopathy, postpartum cardiomyopathy,idiopathic dilated cardiomyopathy, cardiac necrosis, cardiac edema orcardiac fibrosis, and wherein the electronically displaying is carriedout to display the likelihood of the future onset of global cardiacinjury to a workstation having a display associated with a clinician orother user.
 7. The method of claim 6, wherein the first and secondimages are cardiac images, wherein at least one of the first image andthe second images comprise a Magnetic Resonance Imaging (MRI) image, andwherein at least the second image is taken after administration of acytotoxic chemotherapeutic drug to the patient.
 8. The method of claim7, wherein the chemotherapeutic drug is for treating cancer, and whereinthe method further comprises obtaining images at intervals prior to orafter a planned chemotherapeutic drug to evaluate whether myocellularnecrosis is likely to result in a drop in LVEF (left ventricularejection fraction).
 9. The method of claim 7, further comprisingobtaining the second image after administration of doxorubicin toevaluate whether myocellular necrosis is likely to result in a drop inLVEF (left ventricular ejection fraction).
 10. The method of claim 7,further comprising obtaining the second and at least one subsequentimage after administration of anthracycline to evaluate whethermyocellular necrosis is likely to result in a drop in LVEF (leftventricular ejection fraction).
 11. The method of claim 6, furthercomprising electronically determining whether a distribution pattern ofvoxel or pixels of high intensity in a left ventricle myocardium isdistributed rather than clustered to predict whether a myocellularinjury secondary to cytotoxic chemotherapy is likely to be associatedwith a fall in LVEF (left ventricular ejection fraction).
 12. The methodof claim 1, wherein the images are cardiac MRI images of a plurality ofslices of a patient's heart, and wherein the global injury is associatedwith myocardial edema, fibrosis or necrosis that is not visuallydetectable at a resolution of the cardiac MRI images.
 13. A method ofevaluating a potential of a global cardiac injury of tissue of apatient, comprising: electronically evaluating intensity and associatedx, y, z coordinates of pixels/voxels in a plurality of cardiac MR(Magnetic Resonance) image slices of a three dimensional tissue volumeof a left ventricle of the patient of a region of interest in a firstimage and a corresponding region of interest in a second image obtainedafter the first image; electronically applying an autocorrelationstatistic (I) to determine a relationship between a pattern ofpixel/voxel intensity within each image slice of the three dimensionaltissue volume of the left ventricle to evaluate whether the pattern isclustered or distributed; electronically determining if there is ascattered or distributed pattern or a clustered pattern of highintensity pixels/voxels in the region of interest using theautocorrelation statistic; and outputting to a display associated with auser a prediction or evaluation of global injury to tissue in the regionof interest based on the determined pattern of high intensity data,wherein the global injury is associated with a diffuse, scattered ordistributed pattern of high intensity pixels/voxels rather than aclustered pattern.
 14. A method according to claim 13, furthercomprising evaluating a global intensity characteristic of the region ofinterest based on data from the first and second images, whereinevaluating the global intensity characteristic comprises evaluating atleast one of skew, kurtosis, or standard deviation of at least oneproperty of pixels/voxels of the region of interest and/or at least oneof a shape or distribution of at least one pixel/voxel intensityhistogram associated with the region of interest.
 15. A system forpredicting, evaluating and/or detecting global injury in a patient,comprising: at least one processor configured to (i) identify intensityand x, y, z coordinates of each voxel in 3-dimensional space todetermine a global intensity characteristic of a region of interestbased on data from first and second MR (Magnetic Resonance) images,wherein the global intensity characteristic comprises evaluating atleast one of skew, kurtosis, or standard deviation of at least theintensity of pixels/voxels in the region of interest and/or at least oneof a shape or distribution of at least one pixel/voxel intensityhistogram associated with the region of interest and (ii) apply anautocorrelation measure/statistic (I) to determine a relationshipbetween a pattern of high intensity pixels within each image slice todetermine if there is pattern clustering within a ROI (region ofinterest) or a random or diffuse pattern.
 16. The system of claim 15,wherein the first image and the second image comprise cardiac MagneticResonance Imaging (MRI) images if a left ventricle.
 17. A system ofevaluating an actual or potential of a global injury of tissue of apatient, comprising: a circuit with at least one processor configuredto: (i) compare image data derived from a region of interest in a firstimage of tissue with image data derived from a corresponding region ofinterest in a second image of tissue obtained after the first image andidentify image intensity of each voxel and coordinates in threedimensional space; (ii) determine if there is a distributed or scatteredpattern of high intensity voxels and/or pixels in the region of interestby applying an autocorrelation statistic (I) to determine a relationshipbetween a pattern of high intensity pixels within each slice, toevaluate whether the pattern is clustered or randomly distributed ordiffuse; and (iii) output to a display a prediction or evaluation of aglobal injury to tissue in the region of interest to a user based on thedetermined pattern of high intensity data, wherein the global injury isdue to a change in tissue composition and/or function that is in arandom or diffuse distributed pattern and not a clustered pattern and/orin a pattern that is not visually detectable at a resolution of theimages.
 18. The system of claim 17, wherein the first and second imagesof the region of interest are images of at least one of heart, blood,muscle, brain, nerve, skeletal, skeletal muscle, liver, kidney, lung,pancreas, endocrine, gastrointestinal and/or genitourinary tissue. 19.The system of claim 17, wherein the first and second images comprise atleast one of a Magnetic Resonance Imaging (MRI) image, and/or an X-raycomputed tomography image, an ultrasound image, a single photon emissioncomputed tomography (SPECT) image and/or positron emission tomography(PET) image.
 20. A system according to claim 17, wherein the first andsecond images comprise cardiac MR images including image slices of aleft ventricle, and wherein the at least one processor is configured tooutput to the display histogram data associated with image intensitydata of the region of interest derived from the first and second images.21. A system of non-invasively evaluating a patient for injury orabnormality, comprising: a circuit that comprises at least one processorconfigured to a ply an to determine if there is a pattern of a definedat least one voxel characteristic within a three dimensional (3-D)tissue volume of a ROI (region of interest) and analyze the at least onecharacteristic of voxels of MRI image slices to detect a global injury,global abnormal tissue, or global abnormal accumulation of materials notfound in normal ratios within native tissue, even when thecharacteristic of those voxels is in a random pattern or in a patternthat is not visually detectable at a resolution of the MRI image slices,wherein the global injury, global abnormal tissue or global accumulationis identified when there is a determined pattern that is scattered,diffuse and/or randomly distributed in the 3-D volume of the region ofinterest; and a display in communication with the circuit that providesan output of the analysis.
 22. The system of claim 21, wherein theregion of interest is the heart, wherein the circuit is configured toanalyze a global cardiac injury as the global injury, and wherein thecircuit analyzes histograms for skew or kurtosis to identify the globalcardiac injury.
 23. The system of claim 21, wherein the circuit isconfigured to define associated x, y and z voxel coordinates of eachvoxel in the region of interest.
 24. The system of claim 21, wherein theregion of interest is the heart, and wherein the MRI image slicescomprise perfusion images acquired using blood oxygenation leveldependent (BOLD) cardiac imaging.
 25. The system of claim 21, whereinthe circuit is configured to detect a global cardiac injury associatedwith at least one of cardiomyopathy, edema or fibrosis.
 26. The systemof claim 21, wherein the circuit is configured to apply anautocorrelation statistic (I) to carry out the autocorrelation todetermine if there is a pattern of high intensity pixels within eachimage slice, to assess whether a determined pattern is distributed orclustered in the 3-D volume of the region of interest.